Photoredox-Enabled Applications of Primary Amines as Alkylating Reagents

伯胺作为烷基化试剂的光氧化还原应用

• 批准号: 9760408
• 负责人: Jacob Geri
• 金额: $ 6.12万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760408
• 关键词: Affinity; Agrochemicals; Alcohols; Alkenes; Alkynes; Amines; Amino Acids; Ammonia; Ammonium; Architecture; Azides; Binding; Biological; Carbon; Carbon Dioxide; Carboxylic Acids; Catalysis; Cations; Chemicals; Chemistry; Complement; Complex; Copper; Coupling; Crown Ethers; Development; Diazomethane; Electron Transport; Electrons; Esters; Ethers; Gases; Goals; Hydrogen; Hydrogen Bonding; Lead; Methodology; Molecular; Natural Products; Nature; Organic Chemistry; Organic Synthesis; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Preparation; Process; Reaction; Reagent; Research; Structure; System; Time; Transition Elements; Variant; Vertebral column; Work; base; c new; catalyst; chemical reaction; cost; drug discovery; drug efficacy; functional group; improved; side effect; skeletal; small molecule; tertiary amine

PROJECT SUMMARY/ABSTRACT Synthetic organic chemistry is essential for the preparation of complex small molecules used as drugs and agrochemicals, and advances in this field are driven by the discovery of new types of bond-forming chemical reactions. Research in reaction development allows wider pools of starting materials to be used for the construction of complex molecular architectures, and new fragment-coupling reactions which use widely available, bench stable, and biologically prevalent organic functional groups as reactive handles are highly impactful. Catalytic reactions that use such “native” functional groups, such as alcohols, carboxylic acids, and amines, can be immediately and widely deployed in medicinal chemistry settings for both small-scale drug discovery and in large-scale process development settings because of their greater opportunities for molecular diversification and the lower cost of the associated starting materials. In the proposed research, a new reactivity manifold for amines will be developed that will enable their use as electrophilic alkylating reagents in C-C bond forming reactions with ammonia as the sole byproduct. This contrasts with their traditional reactivity profile, which is limited to their use as nucleophiles in C-N bond forming reactions. A dual-catalysis approach is proposed which will use a strongly reducing photoredox catalyst to transfer a single electron to an alkylammonium cation to form an unstable, neutral ammonium radical. Typically, such hypervalent radicals decompose through loss of hydrogen atoms through N-H bond homolysis to generate hydrogen gas after self- annihilation. However, it is proposed that multiple hydrogen bonding interactions between an alkylammonium cation and a crown ether-type organocatalyst can be exploited to stabilize ammonia as a leaving group and bias the reaction pathway towards C-N bond homolysis, releasing a synthetically useful alkyl radical and ammonia. The alkyl radical thus generated will then be captured by organic and inorganic radicalphiles in C-C bond forming reactions proceeding through conjugate addition, radical aromatic substitution, and transition- metal cocatalyzed cross-coupling pathways. The intermediacy of a free alkyl radical makes this methodology highly modular, and it is anticipated that a wide variety of photoredox C-C coupling methodologies can be developed which will merge reductive C-N activation with oxidative C-CO2-, C-OH, and C-H activation.

项目总结/摘要 合成有机化学对于制备用作药物的复杂小分子和 农业化学品，并在这一领域的进展是由发现新型键形成化学品 反应.反应开发中的研究允许更广泛的起始材料池用于反应。 复杂分子结构的构建，以及广泛应用的新型片段偶联反应 作为反应性手柄的可用的、工作台稳定的和生物学上普遍存在的有机官能团是高度 有影响力使用这种“天然”官能团，如醇、羧酸和它们的组合的催化反应， 胺，可以立即和广泛地部署在药物化学设置为小规模药物 发现和大规模工艺开发环境中，因为它们有更大的机会， 多样化和相关起始材料的较低成本。在这项研究中，一个新的 将开发胺的反应性歧管，使其能够用作亲电烷基化试剂， C-C键形成反应，氨作为唯一的副产物。这与它们传统的反应性形成对比 这局限于它们在C-N键形成反应中作为亲核试剂的用途。一种双催化方法是 提出了将使用强还原光氧化还原催化剂将单个电子转移到 烷基铵阳离子形成不稳定的中性铵自由基。通常，这种超价自由基 通过N-H键均裂失去氢原子分解， 歼灭然而，有人提出，烷基铵之间的多个氢键相互作用 阳离子和冠醚型有机催化剂可用于稳定氨作为离去基团， 使反应途径偏向C-N键均裂，释放合成上有用的烷基， 氨由此产生的烷基自由基然后将被C-C中的有机和无机亲自由基捕获 通过共轭加成、自由基芳族取代和过渡- 金属共催化的交叉偶联途径。自由烷基的中间作用使得这种方法学 高度模块化，并且预期可以实现各种各样的光氧化还原C-C偶联方法。 开发了将还原性C-N活化与氧化性C-CO2-、C-OH和C-H活化合并的方法。